Parkinson's disease (PD) involves pathological loss of neurons. The long-term objective of this research in our laboratory is to understand how environmental and genetic neurotoxic agents interact to signal and regulate the survival/apoptosis machinery in PD pathogenesis. A series of our recent findings highlight the key role of nuclear cyclin dependent kinase 5 (CdkS)-mediated inhibition of survival factor myocyte enhancer factor 2 (MEF2) in neuronal survival and apoptosis. Based on this, we propose in the present application to explore the role of nuclear Cdk5-MEF2 pathway in mediating and integrating the toxic signals of PD relevant environmental toxicants and genetic risk factors in the degeneration of dopamine neurons. Our specific aims are: 1. to assess the role of nuclear Cdk5-mediatd regulation of MEF2 in environmental toxicant-induced degeneration of dopaminergic neruosn in cellular models of PD;2. to determine the role of nuclear Cdk5- MEF2 pathway in environmemntal toxicant-induced neuronal loss in animal models of PD;and 3. to establish the role of CDk5-MEF2 pathway in integrating neurotoxic signals of environmental toxicants and alpha- synuclein in genetic models of PD. To accomplish aim Mil, we will test a group of model toxicants including MPP+(metabolite of MPTP), rotenone, and paraquat in dopaminergic neuronal cell line SN4741 cells, primary dopamine neurons, and rodents/transgenic mice to investigate whether de-regulation of nuclear Cdk5 activiy and loss of MEF2 survival promoting function underlie the demise of dopaminergic neurons in response to environmental toxicants. We will attempt to establish whether nuclear Cdk5-MEF2 mediates alpha-synculein toxicity in genetic models of PD pathogenesis and study how toxicant-alpha-synuclein interaction affects this critical signaling pathway. We will use a combination of morphological, biochemical, molecular biological, functional/behavioral and genetic methods in the proposed study. Our studies will allow us to determine whether nuclear Cdk5-MEF2 pathway is a major mediator of environmental toxicant-induced apoptosis of dopamine neurons and functions as a key converging point for the toxic effect of toxicant-alpha- synuclein interaction. This novel insight gained from this study will demonstrate how environmental toxicants and genetic risk factors may converge and disrupt a survival pathway, providing a molecular mecahnism that may underlie loss of dopamine neurons relevant to both sporadic and familial PD.